This invention is in the field of pharmacology, and relates to drugs that can help reduce the frequency, duration, and/or severity of certain types of headaches that are classified as "recurrent primary headaches", including migraine headaches and cluster headaches. The treatment disclosed herein involves daily or other chronic administration of "leukotriene antagonist" drugs, which previously have been used for treating asthma.
As is well-known, migraine headaches (also referred to simply as migraines, for convenience) are severe types of headaches. Typically, migraines are distinguished from ordinary headaches by several factors. Migraines with aura (referred to in the past as "classic" migraines) affect approximately 20% of migraine sufferers, and are usually preceded or accompanied by some type of visual, sensory or motor disturbance, known as an aura. Migraines without aura (previously known as "common" migraines) usually affect one side of head only, last between 4 and 72 hours, and are usually accompanied by nausea, vomiting, or similar symptoms. To establish a diagnosis of migraine without aura, there must have been at least 5 previous episodes; organic factors which may mimic migraine must have been ruled out; and, the attack must last 4 to 72 hours.
"Cluster headaches" were given that name because they tend to occur in episodic clusters, with a cluster cycle usually lasting 4 to 8 weeks. In some patients, a cluster occurs only once in a lifetime; in other patients, a cluster may occur roughly once a year, pith periods of complete remission between attacks; and, in the roughly 10% of patients who are chronic sufferers, there are no significant periods of remission. As opposed to migraines (which occur in women at roughly 3 times the rates as in men), cluster headaches are more prevalent in men than in women, by a factor of about 5:1 or higher.
In cluster headaches, the rain is almost always one-sided, and typically involves the eye and temple region. As opposed to migraine, which may he a throbbing type of pain, the pain of a cluster headache is almost always non-throbbing, and is often likened by the patient to a red hot poker being driven into the affected eye, with immense force. Attacks generally last about 45 to 90 minutes, and may occur several times a day. They also fairly often awaken a sufferer from sleep, when in cycle. Symptoms accompanying such attacks generally include a red and tearing eye, stuffed and running nostril, and drooping of the eyelid, all on the side of the attack. As opposed to migraine patients, who must retreat to a dark and quiet environment, the pain of cluster headaches is usually so intense that the sufferer often paces, rocks, walks about, or does anything else that may help distract him from the pain (including, in many cases, banging his head or fists against the wall, ground, or other object).
Migraines and cluster headaches are both important, well-known, and extensively studied medical problem. In many cases, they completely incapacitate a sufferer for the duration of the headache. Their physiological aspects, causative and aggravating factors, and current Treatments are discussed in detail in numerous scientific articles, and in full-length medical textbooks such as Headache in Clinical Practice (edited by S. Silberstein et al., Oxford Univ. Press, 1998); The Headaches, by J. Olesen; and Headache Disorders: A Management Guide for Practitioners, by A. Rapoport and F. Sheftell (W. B. Saunders, Philadelphia, 1996). In addition, various definitions, categories, and diagnostic standards are defined by standardized criteria that have been approved and issued by the International Headache Society (IHS), which were published as a supplement to the journal Cephalalgia in 1988.
Migraines and cluster headaches are both classified as "recurrent primary headaches". They are recurrent, since they recur with sufficient frequency to seriously interfere with the health and quality of life of a patient, to a point of requiring and demanding medical attention, as opposed to just taking aspirin or similar over-the-counter analgesics and lying down till it passes. They are also regarded as "primary" headaches, since they usually arise as a primary adverse biologic condition, independently of other causative medical conditions such as tumors, sinus or other infections, bleeding problems, etc.
A third major category of recurrent primary headaches is often referred to as "tension" (or "tension-type") headaches. Although these can often be resolved in many patients if the source of the tension can somehow be eliminated or substantially lessened, that approach may require a major lifestyle change for the patient, and is often impractical or impossible for patients who cannot escape from the demands imposed by stressful work, family, or other situations. Accordingly, recurrent tension headaches must often be treated as a medical problem using drug intervention, usually in combination with training in relaxation and stress management techniques. In addition, many researchers and physicians believe that tension headaches and migraine headaches exist on a continuum, and involve the same or overlapping neurobiological mechanisms. It should also be noted that various drugs (including anti-inflammatory drugs, such as certain types of prostaglandin antagonists) that are effective (in at least some patients) in treating migraine headaches are also effective in treating tension headaches as well. Because of their similarities and overlapping factors, it is believed by the Applicant that tension headaches may be susceptible to effective treatment, in at least some sufferers, using leukotriene antagonist drugs as disclosed herein.
There are at least three "aspects" or "traits" of primary recurrent headaches that are important in this invention, since these traits can provide quantifiable evidence of whether a treatment is or is not effective in controlling such headaches. Those three aspects are: (1) frequency, which is usually evaluated over a span of time, such as number of such headaches per week, per month, or per year; (2) duration, which evaluates (usually in hours) how long a headache lasts, from the time it begins to develop into a migraine or cluster headache, until it has been resolved; and, (3) severity (also referred to as intensity), which is based on subjective estimates of the severity or intensity of pain or other side effects (such as nausea) being suffered by patients during such headaches.
If a preventive drug treatment can significantly reduce any one of these three aspects (frequency, duration, or severity), even if it has no noticeable effects on the other two aspects, then the preventive treatment can and should be regarded as effective, successful, and beneficial to patients, since that treatment can substantially improve the quality of life for such patients.
For obvious reasons, an ideal preventive treatment would reduce all three aspects; and, indeed, the preventive treatment disclosed herein does indeed appear to accomplish that ideal goal, in at least some patients, based on an initial open-label trial. However, it must be noted that simultaneously reducing all threes aspects of headaches is not essential to providing useful and effective relief from severe headaches. A treatment which can reduce any one (or two) of those goals is effective and useful from a medical perspective, and will be enthusiastically welcomed by sufferers of migraine and/or cluster headaches (and by their families and friends).
Migraines are more common than cluster headaches, and have been studied more extensively. In addition, a better and more effective set of drugs have been developed to treat migraines, than cluster headache. For those reasons, the discussion below focuses mainly on migraines, rather than cluster headaches. However, because of various physiological and pharmacological factors, and because of the highly positive results observed so far in initial tests on migraine sufferers, it is believed by the Applicant that chronic treatment with leukotriene antagonist drugs, as disclosed herein, is also likely to provide significant benefits to at least some patients who suffer from cluster headaches, or from other types of recurrent primary headaches that do not respond adequately to other previously-known treatments.
Physiology of Migraines; Triptan Drugs
The factors that trigger or aggravate migraines vary widely among different patients. In some patients, for example, migraines are triggered by eating certain foods, such as chocolate, red wine, MSG, artificial sweeteners, or various types of aged cheese; in some patients, migraines can be triggered by perfumes or other compounds that generate odors; and in women, migraines often accompany menstruation.
Regardless of which factors trigger or aggravate migraines in any specific patient, migraine is ultimately believed to be a neurobiological disorder, with familial and genetic factors. It is believed that most cases involve a cascade of events beginning in the cortex region of the brain, with electrical changes possibly related to a phenomenon known as Cortical Spreading Depression (CSD), and cascading down to structures in the brainstem (most notably the Raphe Nuclei) which are rich in serotonergic projections. The hypothalamus and trigeminal caudate nucleus (the main relay station for head pain, located in the lower brainstem) are also involved. As a result of this process, the trigeminal vascular system is activated, causing vasodilataion and inflammation of small arteries that penetrate the dura mater. As a result of vasodilatation and what is known as "neurogenic inflammation", inflammatory and pain mediators are secreted (including Substance P, various kinins, histamine, and "calcitonin gene related peptide"), sending pain signals to the thalamus and on to the cortex. Thus, changes in blood vessels are believed to be manifested as a final common pathway, from a complex cascade of events that begin in he cortex and involve numerous structures, pathways, aid neurotransmitters in the brain.
It should also be recognizes that the pathophysiology of migraines involves both central nervous system (CNS) and peripheral pathways. The peripheral pathways involve blood vessels, as described above, while the CNS pathways involve the cortex, and brainstem structures such as the Raphe Nuclei and the trigeminal caudate nucleus.
Drug treatments for migraine headaches have improved substantially during the past few years, with the widespread introduction and use of drugs known as the "triptans". These include sumatriptan (sold under tradenames such as Imitrex and Imigran by Glaxo-Wellcome, and also used to treat cluster headaches), naratriptan (sold under the tradenames Amerge and Naramig, also by Glaxo-Wellcome), zolmitriptan (sold under the name Zomig, by Zeneca Pharmaceuticals), and rizatriptan (sold under the name Maxalt, by Merck). All of these are available as tablets for oral ingestion; in addition, for patients who suffer from nausea, several of these drugs are also available in other forms, such as subcutaneous injectable formulations, nasal sprays, and wafers or trochas designed to dissolve in the mouth.
The primary mode of action of all of these "triptan" drugs is believed to involve selective activation of certain serotonin receptors subtypes, primarily 5HT-1B receptors (which are present on blood vessels) and 5HT-1D receptors (which are present on nerve cell terminals, both peripherally and in the CNS).
Serotonin is the common name for 5-hydroxytryptan, abbreviated as 5-HT. In the CNS, 5-HT is a neurotransmitter molecule, which is generally inhibitory, since it suppresses (rather than activates) nerve signals in neurons. In vascular tissue, sumatriptan and other "triptan" drugs generally cause constriction of blood vessels in the cerebral region, and help to reverse neurogenic inflammation around those blood vessels during migraine attacks.
Lack of Effective Preventive Treatments
In general, the triptan drugs (and other therapies that are suited for acute treatment of migraines) cannot be used as preventive strategies, for a number of reasons. Two of the primary reasons are: (1) standard preventive pharmacologic treatment (involving analgesics such as aspirin and ibuprofen, ergotamine and its derivatives, etc.) simply does not work in the large majority of migraine patients; and (2) chronic administration of acute therapy (such as the triptan drugs) to migraine patients often drives a patient into a state where the patient suffers "rebound" headaches and/or chronic headaches. Indeed, chronic administration of triptan drugs has been observed to generate "transformed" migraine headaches which occur daily, as discussed in Neurologic Clinics: Advances in Headache (N. T. Mathew, editor; W. B. Saunders, Philadelphia, Pa., 1997).
In addition, triptan drugs can pose a risk of adverse cardiovascular events, such as heart attack, stroke, etc., so they are contraindicated in patients suffering from heart disease, stroke, uncontrolled hypertension, basilar or hemiplegic migraine, and in people who are taking various other drugs, such as monoamine oxidase inhibitors. Accordingly, before triptan drugs can be prescribed safely, the diagnosing physician must do a risk factor analysis for various potential cardiovascular disorders, especially among patients who may be overweight who smoke, or who suffer from high cholesterol, inadequate exercise levels, hypertension, a family history of heart disease or stroke, etc. Clearly, the risks involved in any such analysis would increase substantially if a doctor or patient were tempted to use triptan drugs as a chronic treatment.
In addition, toxicity syndromes may result, e.g. ulcers, other gastrointestinal bleeding, and "8th nerve" toxicity when aspirin is used chronically, hepitotoxicity if acetaminophen is use chronically, and various types of kidney damage (it has been estimated that 10% of all end-stage kidney disease is secondary to the overuse of over-the-counter non-steroidal medications). Addiction also may occur with prescription pain-killers such as butalbital products (Fiorinal, Fioricet, Esgic, etc.) or opiates (Percocet, Percodan, Codeine, Stadol, etc.). Most efforts at chronic preventive treatment also result in undesired side effects, such as fatigue, decreased energy, depression, weight gain, decreased libido, dry mouth, cardiac arrhythmias, hair loss, tremors, hepatotoxicity, etc. Most do not maintain their efficacy over sustained periods of time, and a number of such therapies require periodic monitoring of blood (including complete blood count (CBC), platelet counts, blood urea nitrogen levels, creatinine, and cholesterol levels), as well as tests to ensure that liver and/or kidney functioning has not been impaired.
In view of the important advances and options offered by the recent development of triptan drugs, it is widely agreed among headache specialists that preventive therapies have not kept pace with advances in acute therapy. All of the preventive strategies are associated with potentially serious limitations, adverse events, and side effects, all of which makes their use unattractive to doctors and patients. Even when a preventive therapy is deemed to be suitable for testing in a specific patient, the results usually show, at best, only about a 50% decrease in frequency and intensity, in about half of the patients tested on such treatment regimens.
In general, the best preventive approach that treating physicians can take under the prior art involves efforts to control any potential triggering factors (such as careful screening of the patient's diet and environment to identify triggering factors, so the patient can take extra precautions to avoid them), and treatment of any concomitant medical problems that may help trigger migraines. For example, anti-depressants are often prescribed for patients whose migraines appear to be triggered or aggravated by depression, and beta-blockers (which help regulate heartbeat rates) are prescribed for patients whose migraines appear to be triggered by fluctuations in blood pressure or heartbeat. Beta-blockers are the most commonly prescribed treatment that might be regarded as a preventive treatment for migraine. However, beta-blockers are contraindicated in patients with asthma, and there is a high correlation between asthma and migraines; roughly 20% of asthmatic patients suffer from migraines.
For various similar reasons, there also are no truly effective strategies for preventing cluster headaches.
In summary, there is a severe and very serious lack of effective and adequate preventive treatments, to reduce the frequency, duration, and/or severity of migraine or cluster headaches. Accordingly, there is a major medical need for effective preventive drug treatments that can be used in a chronic and long-term manner to prevent migraine or cluster headaches (rather than just for treating them once they have commenced), and to reduce their duration and severity when they do arise.
In addition, there is also in important medical need for improved drug treatments that can decrease the amount of pain and suffering caused by migraine or cluster headaches, once they begin. One such form of treatment would involve administration of a drug that can help reduce migraine symptoms in patients who are not adequately helped by the triptan class of drugs. Another such treatment would involve coadministration of two completely different types of drugs, which would work by completely different and independent mechanisms, to provide better pain relief than either class of drug can provide by itself.
Background Information on Leukotrienes
The subject invention involves drugs that act as "leukotriene antagonists". To the best of the Applicant's knowledge and belief, these drugs have never previously been used to treat or prevent migraine headaches or cluster headaches; instead, they are used to treat asthma. However, they have become of interest herein, and the activities of various subclasses of leukotrienes have been known since the early 1980's; also, various leukotriene antagonist drugs are known and available. Accordingly, this section provides background information on leukotrienes, and on drugs that are used to reduce leukotriene activity in asthma patients.
Leukotrienes are naturally-occurring molecules that function as inter-cellular messengers in mammals. There are several subtypes, referred to by designations such as LTA.sub.4, LTB.sub.4, LTC.sub.4, LTD.sub.4, and LTE.sub.4, as discussed below.
All of these subtypes are formed from arachidonic acid, a molecule containing 20 carbon atoms, which has four internal double bonds near the center of the chain and a carboxylic acid group at one end. Arachidoric acid is continuously synthesized at cell membranes, by cleavage of certain types of phospholipids. This cleavage reaction is catalyzed by phospholipase enzymes. The free arachidonic acid is then converted into any of four different types of compounds, which are leukotrienes, prostaglandins, prostacyclins, and thromboxanes. All four of these types of compounds are called "eicosanoids".
Prostaglandins, prostacyclins, and thromboxanes all contain cyclic structures, and are created when "cyclooxygenase" enzymes (often abbreviated as COX enzymes) generate these cyclic structures from the carbon chain in arachidonic acid. Recently developed "COX inhibitor" drugs are approaching public use and sale; these apparently can inhibit certain types of pain (including arthritis pain) that cannot be treated adequately with previously known drugs.
By contrast, leukotrienes are created by the action of different types of enzymes. Initially, one of the four double bonds in arachidonic acid is converted into an epoxide structure; the three double bonds that remain give leukotrienes the "tri-ene"classification. The epoxide structure in LTA.sub.4 is relatively reactive and unstable, so LTA.sub.4 serves mainly as a precursor during synthesis of the other leukotrienes. LTB.sub.4 is generated ashen the epoxide form is been hydrolyzed into a di-hydroxy compound, while LTC.sub.4, LTD.sub.4 and LTE.sub.4 are all modified by the addition of cysteine, an amino acid that contains a relatively reactive sulfhydryl group (--SH) at the end of a spacer chain.
All of the eicosanoid compounds tend to aggravate inflammatory, pain, and fever responses, and they have been the targets of extensive research on anti-inflammatory and analgesic drugs. For example, anti-inflammatory steroids such as cortisone function by suppressing the phospholipase enzymes that generate arachidonic acid from membrane phospholipids. Pain-killers such as aspirin and ibuprofen act by blocking (to some extent) the cyclooxygenase enzymes that control the conversion of arachidonic acid to prostaglandins, prostacyclins, and thromboxanes.
Leukotrienes have been recognized as inflammatory agents since the early 1980's. Articles that focus on the specific cellular activities of the various leukotrienes include Smith et al 1980, Ford-Hutchison et al 1980, Bray et al 1981, Lewis 1981, Gimbrone et al 1984, and Levine et al 1984 (complete citations to articles are provided below). Review articles from that period include Bray 1993 and Piper 1984.
In the 1990's, various drug; known as "leukotriene antagonists" were identified, which can suppress and inhibit the activity of leukotrienes in the body.
The term "leukotriene antagonist" is used herein in the conventional medical sense, to refer to a drug that suppresses, blocks, or otherwise reduces or opposes the concentration, activity, or effects of one or more subtypes of naturally occurring leukotrienes. In laymen's terms, LT antagonists can be referred to as LT blockers.
LT antagonist drugs can wore by any of at least three distinct mechanisms: (i) by inhibiting the enzymes that convert arachidonic acid into leukotrienes; (ii) by competitively occupying leukotriene receptors on the surfaces of cells, thereby making those receptors unavailable to react with leukotrienes, without triggering ("agonizing") the cellular reactions that are triggered by leukotrienes; or (iii) by binding to leukotriene molecules in blood or other body fluids, thereby entangling or altering the leukotriene molecules and rendering them unable to trigger leukotriene receptors.
Two leukotriene (LT) antagonist drugs have become successful and widely used treatments for asthma, since they can help suppress the bronchial and alveolar constrictions that cause or aggravate asthma attacks. Those two drugs are: (i) zafirlukast, which is sold under the tradename "Accolate" by Zeneca Pharmaceuticals (Wilmington, Del.), and (ii) montelukast, sold under the tradenames "Singulair" by Merck and Company (West Point, Pa.). Various other LT antagonist drugs are also known, such as pranlukast (discussed in Hamilton et al. 1998), BAYx7195 (discussed in Boulet et al. 1997), LY293111 (discussed in Evans et al. 1996), ICI 204,219 (discussed in Taylor et al. 1991, Dahlen et al. 1991, and other articles), and ONO-1078 (discussed in Taniguchi et al. 1993). All of these LT antagonist drugs listed above are believed to help control and suppress asthma attacks primarily by competitive binding to (and blocking of) one or more types of leukotriene receptors on bronchial cells and various types of blood cells.
In addition, various drugs are known which can inhibit the synthesis of LT molecules, by inhibiting one or more of the lipoxygenase enzymes that synthesize LT molecules. Such drugs include BAYx1005 (discussed in Hamilton et al. 1997 and Dahlen et al. 1997), MK-886 (discussed in Friedman et al. 1993), MK-0591 (discussed in Diamant et al. 1995), ZD2138 (discussed in Nasser et al. 1994), and zileuton (also known as A-64077, discussed in Hui et al. 1991 and in Knapp 1990).
The effects of these drugs on asthma sufferers are discussed in various articles such as Busse 1996 (a review article) and other articles cited therein, and in a number of articles published after that review, such as Evans et al. 1996, Roquet et al. 1997, Boulet et al. 1997, Dahlen et al. 1997, and Hamilton et al. 1997 and 1998.
Accolate and Singulair are both sold in pill form, and can be taken every day for long periods of time. Rather than creating tolerance or dependence problems, these drugs appear to help suppress and reduce ongoing asthma problems, when taken chronically, by helping suppress the hypersensitive immune or allergic responses that often grow cumulatively worse in people who suffer from unwanted and excessive activity of the allergic or other immune systems.
As noted above, leukotriene antagonists have not previously been used to treat or prevent migraine or cluster headaches. Instead, there is a major medical need for a treatment that can be used on a chronic and long-term basis, to prevent migraine and/or cluster headaches. This is a very serious, important, and unmet medical need; the seriousness and importance of this unmet need have been known for decades, by the millions of people who suffer from the intense pain of severe and debilitating migraine headaches, and by the thousands of physicians and researchers who have been looking for decades for such a treatment without success.
Accordingly, one object of the subject invention is to disclose and provide a method for long-term and chronic yet safe administration of a drug that can prevent migraine or cluster headaches, and which can reduce their frequency in a patient who suffers from such headaches.
Another object of this invention is to disclose and provide a method for long-term and chronic administration of a drug that can reduce the duration and/or severity of migraine or cluster headaches, when they do arise.
Another object of this invention is to disclose and provide a method for treating migraine headaches among patients who are not adequately and effectively treated by "triptan" drugs such as sumatriptan, naratriptan, zolmitriptan, and rizatriptan.
Yet another object of this invention is to disclose and provide a method for coadministering two different types of drugs, which work by completely different and independent mechanisms, to provide better pair relief for migraine and cluster headaches than either drug can provide by itself.
These and other objects of the invention will become more apparent through the following summary and description of the preferred embodiments.